Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder characterized by unexplained left ventricular hypertrophy (LVH), which can lead to heart failure, arrhythmias, and sudden cardiac death (SCD), particularly in young individuals (Argirò et al., 2025; Marian, 2021). The prevalence of HCM, when defined by the presence of LVH, is estimated to be between 1:300 and 1:600. However, when genetic testing and family screening are incorporated, the estimated prevalence reaches approximately 1:250 in the general population (Marian, 2021). Clinical presentation is markedly heterogeneous, ranging from lifelong asymptomatic status to severe complications such as heart failure, atrial fibrillation, embolic stroke, and SCD—a spectrum that has long posed substantial challenges for clinical management (Argirò et al., 2025; Marian, 2021; Sikand et al., 2025).

The genetic basis of HCM was first established over 3 decades ago with the identification of a missense mutation in the β-cardiac myosin heavy chain gene, defining HCM as a “disease of the sarcomere” (Geisterfer-Lowrance et al., 1990; Calore et al., 2025). Nevertheless, pathogenic variants in genes encoding cardiac sarcomeric proteins are detected in only 30%–40% of cases, while more than 50% of clinically diagnosed HCM patients lack identifiable sarcomeric mutations (Lopes et al., 2024). More than 20 genes have been implicated in HCM, including MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, ACTN2, ALPK3, and FHOD3, which exhibit autosomal dominant inheritance with variable penetrance and diverse expression (Choi et al., 2025). Among these, the first eight sarcomeric genes remain the most strongly associated, accounting for over 90% of genotype-positive cases (Lopes et al., 2024; Choi et al., 2025; Ingles et al., 2019; Tadros et al., 2025).

Clinical manifestations of HCM arise from complex interactions between genetic and non-genetic factors, with genetic architecture playing a predominant role in shaping phenotypic heterogeneity (Marian, 2021). The specific gene involved, the type and location of the mutation, and the presence of multiple variants—such as compound heterozygosity—significantly influence age of onset, extent of hypertrophy, risk of left ventricular outflow tract obstruction, and overall prognosis (Marian, 2021; Lopes et al., 2024; Wang et al., 2025; Maron et al., 2022). Therefore, delineating genotype–phenotype correlations is not only academically relevant but also a clinical imperative, forming the basis for early diagnosis, improved risk stratification, cascade screening of at-risk relatives, and the development of individualized therapeutic strategies. This narrative review integrates current advances in the genetic basis and phenotypic features of HCM, with a focus on the mutational spectrum and clinical implications of key pathogenic genes. It also summarizes the genetic and phenotypic characteristics of pediatric HCM and examines the influence of ethnicity and sex on HCM phenotypes.

A comprehensive search was conducted in PubMed and Web of Science, supplemented by hand-searching the reference lists of key publications. The search focused on studies published between 1990 and 2025, using combinations of terms such as “Hypertrophic cardiomyopathy”, “gene”, “genotype–phenotype”, “pathogenesis”, and “clinical management”. Both original research and review papers were considered if they were relevant to our research question. Inclusion criteria were: Clinical or mechanistic relevance; High methodological quality; and contribution to understanding genetic spectrum, genotype–phenotype correlations, or clinical implications. Studies with insufficient methodological clarity, duplicated data, or lacking relevance were excluded.

Among genes implicated in HCM, MYBPC3 and MYH7 are the two most prevalent, together accounting for approximately 70%–80% of genetically confirmed cases and about 35% of all clinically diagnosed HCM cases (∼20% for MYBPC3, ∼15% for MYH7) (Chiswell et al., 2023). MYBPC3 encodes cardiac myosin-binding protein C, while MYH7 encodes the β-myosin heavy chain; both are critical components of the thick filament in the cardiac sarcomere, essential for maintaining contractile integrity. Remaining pathogenic variants primarily involve other thick filament genes (e.g., MYL2, MYL3), thin filament proteins (e.g., TNNT2, TNNI3, TNNC1, ACTC1), and Z-disc or cytoskeletal components (e.g., MYOZ2, ACTN2, TCAP). These genes collectively contribute to sarcomere structure, contractile regulation, calcium sensitivity, and mechanosensory signaling (Choi et al., 2025; Walsh et al., 2017; García-Hernández et al., 2024).

Mutations in troponin complex genes (e.g., TNNT2, TNNI3, TNNC1) are detected in approximately 10% of genotype-positive cases, while mutations in ACTC1 and myosin light chain genes (MYL2, MYL3) collectively account for less than 5%–10%. Overall, pathogenic sarcomeric variants explain roughly 60%–70% of familial HCM cases (Choi et al., 2025).

Individuals carrying pathogenic or likely pathogenic sarcomeric mutations tend to develop HCM earlier, exhibit higher penetrance, and face a two-fold greater risk of arrhythmias, SCD, and other adverse cardiovascular events compared with mutation-negative individuals (Nakashima et al., 2020; Ho et al., 2018). Here, we summarized the epidemiological characteristics of pathogenic genes in HCM (Supplementary Table S1; Figure 1).

The MYL2 and MYL3 genes encode the regulatory and essential myosin light chains, which fine-tune myosin ATPase activity and cross-bridge cycling. Pathogenic variants are rare, accounting for ∼1% of HCM cases (Blankenburg et al., 2014; Kabaeva et al., 2002), and are typically associated with apical or atypical hypertrophy, sometimes with familial inheritance. Although uncommon, these variants confer adverse outcomes and more severe progression than MYBPC3 or MYH7 mutations (Ahmad et al., 2022). Mechanistically, altered light chain phosphorylation affects sarcomeric energetics and contractile efficiency, amplifying disease severity.

Mutations in TNNT2, TNNI3, ACTC1, and TPM1 disrupt calcium-dependent regulation of actin–myosin interaction, contributing to diverse HCM phenotypes.

Beyond thick and thin filament proteins, several Z-disc and cytoskeletal genes act as established contributors or modifiers of HCM. ALPK3 variants cause a distinct apical hypertrophy pattern (Zhou et al., 2023; Phelan et al., 2016; Almomani et al., 2016; Cheawsamoot et al., 2020; Lopes et al., 2021), defining a morphologically unique HCM subtype. TTN and OBSCN mutations lead to diffuse or uniform myocardial hypertrophy, implicating cytoskeletal disruption rather than classical sarcomeric dysfunction (Zhou et al., 2023; Saha et al., 2025; Wu et al., 2021). Other rare but relevant genes include FHOD3 (Ochoa et al., 2018), ACTN2 (Bagnall et al., 2014; Prondzynski et al., 2019; Noureddine et al., 2025), TRIM63 (Salazar-Mendiguchía et al., 2020a; Bonanni et al., 2026), PLN (Ceholski et al., 2012; Young et al., 2015; van Drie et al., 2025), CSRP3 (Geier et al., 2008; Salazar-Mendiguchía et al., 2020b), FLNC (Valdés-Mas et al., 2014; Verdonschot et al., 2020; Cui et al., 2018), JPH2 (Parker et al., 2023; Landstrom et al., 2007), and KLHL24 (Hedberg-Oldfors et al., 2019), each affecting sarcomeric architecture, calcium homeostasis, or mechanotransduction in specific contexts.

Patients without detectable sarcomeric mutations often show greater left ventricular outflow tract (LVOT) obstruction despite less hypertrophy (Sedaghat-Hamedani et al., 2018). Interestingly, carriers of double or compound mutations do not consistently exhibit more severe phenotypes than single-variant or genotype-negative patients, suggesting potential epistatic or compensatory interactions (Ahmad et al., 2022).

Pediatric hypertrophic cardiomyopathy (PHCM) is the second most frequent primary myocardial disorder in children and adolescents and a leading cause of sudden cardiac death among young athletes. Unlike adult-onset HCM, which often presents as isolated LVH, PHCM exhibits greater phenotypic and etiological heterogeneity. Underlying causes include inborn errors of metabolism, neuromuscular and malformation syndromes, and genetic mutations affecting sarcomeric proteins—the latter accounting for most apparently idiopathic cases (Moak and Kaski, 2012).

In pediatric cohorts, pathogenic variants in MYBPC3 and MYH7 are the predominant molecular causes, similar to adults (Darwish et al., 2020). Approximately 63.6% of affected children carry a detectable pathogenic or likely pathogenic variant, a rate higher than in adults (Nguyen et al., 2022). Importantly, children with a positive genetic result are more likely to exhibit extracardiac manifestations (38.1% vs. 8.3%) and have increased clinical severity, reflected by higher rates of implantable cardioverter-defibrillator implantation (23.8% vs. 0%) and heart transplantation (19.1% vs. 0%) (Wanert et al., 2023). These findings indicate that genetic status influences not only disease onset but also progression and prognosis in PHCM.

Growing evidence supports a strong relationship between genotype, diastolic function, and clinical outcomes in pediatric HCM(90). Specific allelic variants, such as the VEGF1 963 GG allele, have been associated with reduced left ventricular systolic and diastolic performance (Pieles et al., 2021), suggesting that subtle genetic modifiers may influence myocardial mechanics even in the absence of classical sarcomere mutations. Furthermore, diffuse interstitial fibrosis is common in pediatric patients and likely underrecognized, though its association with long-term outcomes remains inadequately characterized (Nguyen et al., 2022; Hussain et al., 2015).

From a molecular standpoint, MYH7 variants play a pivotal role in early-onset disease. Missense mutations such as p. R719W, p. R453C, and p. Y386C have been linked to a spectrum of presentations, from non-obstructive and restrictive phenotypes to severe conduction defects and SCD (Vasilescu et al., 2018; Mathew et al., 2018; Bobkowsk et al., 2007; Greenway et al., 2012). Additionally, MYH7-related congenital heart diseases (CHD) in children frequently co-occurs with structural anomalies including ventricular septal defect, Ebstein anomaly, hypoplastic left heart syndrome, double-outlet right ventricle, left ventricular noncompaction, and arrhythmias (Kuroda et al., 2022). Collectively, these observations emphasize that MYH7-associated pediatric cardiomyopathy exhibits greater clinical heterogeneity and more aggressive progression than adult-onset cases. Regarding disease onset, metabolic and syndromic forms typically present in infancy or early childhood, while neuromuscular-related HCM often appears in adolescence (Moak and Kaski, 2012). Infants are commonly identified during evaluation for a cardiac murmur or heart failure symptoms, whereas older children may come to attention due to abnormal electrocardiogram (ECG) findings, exertional intolerance, or family screening.

PHCM that persists into adulthood is predominantly driven by pathogenic sarcomeric gene mutations acting in an autosomal dominant manner, most commonly involving MYH7 and MYBPC3(88–91). These pathogenic variants constitute the primary disease-causing determinants and are sufficient to initiate early myocardial hypertrophy, diastolic dysfunction, and progressive remodeling. However, the clinical manifestation of these mutations is often age-dependent and influenced by incomplete penetrance and variable expressivity, which may explain why some individuals carrying pathogenic variants do not exhibit overt hypertrophy or symptoms during childhood and only present with HCM in adulthood. In contrast, non-mutagenic or modifier genes do not independently cause PHCM but may synergistically modulate phenotypic expression, disease severity, and clinical trajectory. Evidence indicates that genetic modifiers, such as specific allelic variants including VEGF1 963 GG, can influence myocardial systolic and diastolic performance even in the absence of classical sarcomeric mutations, suggesting a role in modifying disease penetrance and progression (Pieles et al., 2021). Furthermore, children carrying pathogenic sarcomeric mutations demonstrate higher rates of extracardiac involvement, adverse clinical outcomes, and need for advanced interventions compared with genotype-negative patients, underscoring the dominant contribution of pathogenic mutations to disease severity and prognosis (Wanert et al., 2023). Recessive and dominant inheritance patterns are mainly observed in metabolic or syndromic cardiomyopathies presenting in infancy or early childhood and rarely account for PHCM cases that persist into adulthood (Moak and Kaski, 2012; Monda et al., 2021).

Risk stratification in PHCM remains a major clinical challenge. Heterogeneous genetic background, variable expressivity, and age-dependent penetrance complicate risk prediction. Therefore, comprehensive family-based genetic evaluation—including screening of first-degree relatives and at-risk family members—is strongly recommended, given the predominance of familial aggregation in pediatric cases (Moak and Kaski, 2012; Monda et al., 2021). Early identification of high-risk genotypes, especially in MYH7 or MYBPC3, is essential for timely intervention and tailored management (Table 2).

Sex-specific differences represent another major dimension of phenotypic variability in HCM. Women are generally diagnosed at an older age and have smaller left ventricular volumes but worse diastolic function, often presenting with more severe symptoms such as exertional dyspnea, fatigue, and limited exercise capacity (Constantine et al., 2020; Bonaventura et al., 2021). Despite less pronounced hypertrophy, women frequently exhibit obstructive physiology, leading to a higher incidence of heart failure symptoms and poorer clinical outcomes.

In contrast, men tend to present earlier in life, with greater ventricular mass, wall thickness, and cavity dilation, suggesting sex-linked differences in cardiac remodeling. Hormonal factors, particularly estrogen and androgen signaling, may modulate myocardial fibrosis and calcium handling, contributing to these divergent phenotypes (Constantine et al., 2020). TNNI3 mutations are more frequent in females, whereas MYBPC3 and TNNT2 mutations, as well as mutation-negative cases, are more common in males (Sedaghat-Hamedani et al., 2018). Notably, even after adjusting for genotype, female sex remains an independent predictor of increased mortality and progression to advanced heart failure, underscoring its impact on long-term myocardial performance (Chou and Chin, 2021) (Table 4).

HCM is characterized by marked genetic heterogeneity, with over 1,500 known pathogenic or likely pathogenic variants identified in more than 30 sarcomeric and related genes. However, clear one-to-one correlations between specific mutations and phenotypes remain limited, as many variants are “private” and demonstrate variable penetrance among individuals and families (Bonaventura et al., 2021). Among these, MYBPC3 mutations often show age-dependent penetrance, with carriers developing disease later in life, whereas MYH7 mutations are associated with earlier onset and more severe hypertrophy.

Patients harboring pathogenic or likely pathogenic variants often show higher cardiovascular mortality, increased stroke risk, greater heart failure progression, and elevated SCD risk (Bonaventura et al., 2021). Although rare (∼2.8%), compound or double heterozygous mutations are linked to more severe left ventricular dysfunction and increased heart failure risk, suggesting a possible gene-dose effect.

Beyond classical sarcomeric variants, epigenetic and environmental modifiers play crucial roles in shaping disease expression. DNA methylation patterns, microRNA regulation, and external factors such as hypertension, obesity, diabetes, renal dysfunction, and physical activity all modulate phenotypic expression and disease progression. Together, these elements underscore that HCM is not merely a single-gene disorder but a multifactorial disease where genetic, epigenetic, hormonal, and environmental factors interact to define individual risk and prognosis.

Pharmacological therapy of HCM remains the cornerstone of symptom management across all ages (Argirò et al., 2025; Dicorato et al., 2025). β-blockers, including atenolol and nadolol, are first-line agents that reduce heart rate, myocardial contractility, and improve diastolic filling, while non-dihydropyridine calcium channel blockers such as verapamil and diltiazem serve as second-line therapy when β-blockers are ineffective or contraindicated. Persistent symptoms may be treated with the Class 1A antiarrhythmic disopyramide, and targeted myosin modulators such as mavacamten and aficamten have emerged to limit myosin–actin cross-bridge formation, reduce LVOT gradients, and improve outcomes. Gene-based interventions, though experimental, hold potential to modify the underlying genetic substrate, and invasive strategies including septal reduction surgery or alcohol septal ablation are indicated in severe or refractory cases (Argirò et al., 2025; Sikand et al., 2025; Dicorato et al., 2025; Coylewright et al., 2024). Pediatric HCM requires consideration of body size–adjusted ventricular wall thickness (Lipshultz et al., 2019) and disease heterogeneity, from rapidly progressive early-onset forms to milder adult-like phenotypes (Argirò et al., 2025; Arbelo et al., 2023). Most cases are genetic, and cause-specific diagnosis is increasingly relevant given therapies such as α-glucosidase replacement or gene transfer for Pompe disease, dasatinib and trametinib for Noonan syndrome–associated HCM, and mavacamten (Colella and Mingozzi, 2019; Yi et al., 2016; Mussa et al., 2021; Andelfinger et al., 2019; Ho et al., 2020; Spertus et al., 2021). Genotype-positive, phenotype-negative children and first-degree relatives require echocardiographic surveillance every 1–2 years in adolescence and every 3–5 years in adulthood, with early evidence supporting diltiazem or valsartan in selected cases (Ommen et al., 2020; Ho et al., 2017; Ho et al., 2021; Ho et al., 2015; Ho et al., 2016). Symptomatic management focuses on reducing LVOT obstruction via β-blockers and calcium channel blockers, with limited pediatric experience for disopyramide (Maron et al., 2003; Bogle et al., 2023).

This review provides a systematic synthesis of advances in the genetics and clinical research of hypertrophic cardiomyopathy (HCM). Its main contributions include: First, it constructs a multidimensional knowledge framework encompassing the pathogenic gene spectrum, genotype–phenotype correlations, population heterogeneity, and pediatric characteristics, thereby updating the comprehensive understanding of HCM complexity. Second, through cross-population comparisons, it reveals systematic differences in clinical phenotypes, genetic testing, and treatment patterns between Asian and European patients, while clarifying distinct genetic features in specific populations (such as the United States, Indian, Brazilian, Icelandic, Japanese, Vietnamese, South African, Finnish, and Egyptian cohorts), thereby deepening the understanding of disease specificity across populations. Third, it systematically outlines the unique aspects of pediatric HCM in terms of etiology, clinical presentation, and prognosis, offering a basis for precise management of this subgroup. Fourth, by summarizing the risk profiles associated with different genotypes, it provides direct references for clinical risk stratification, family screening, and individualized interventions, while also identifying current challenges and future research directions. This review offers a significant theoretical foundation and knowledge base for advancing HCM from generalized understanding toward precision medicine practice.

Despite significant progress, the path toward precision medicine in HCM faces several persistent challenges. The clinical interpretation of variants of uncertain significance remains a major dilemma, necessitating functional validation and larger population datasets for definitive classification. Furthermore, the considerable phenotypic heterogeneity observed even among carriers of identical mutations underscores the influence of undiscovered genetic modifiers, epigenetic regulation, and environmental factors, whose complex interactions warrant deeper investigation. While targeted therapies such as myosin inhibitors represent promising advances, translating genetic insights into effective, individualized treatment strategies remains an ongoing endeavor. Ultimately, the development of robust risk prediction models through the integration of genetic, clinical imaging, biomarker, and multi-omics data is crucial for enhancing prognostic accuracy and realizing the full potential of precision care in HCM.

Future research should focus on elucidating the mechanisms of phenotypic modulation through large prospective cohorts and novel technologies (e.g., multi-omics), advancing the clinical interpretation of variants of uncertain significance, and exploring targeted therapies for specific molecular pathways. The ultimate goal is to achieve truly personalized management of HCM, optimizing patient outcomes.